Welcome to your weekly digest of approaching regulatory and clinical readouts. In the second quarter Ionis will report phase III data on its antisense project Ionis-TTRRx in the Neuro-TTR trial, which is key to determining its partner Glaxosmithkline’s involvement with the project after previous safety issues.
Also Novartis expects pivotal trial readouts from its Lucentis follow-on RTH258. The company hopes to challenge Eylea by offering a better dosing frequency, though analyst forecasts have been heading south, highlighting a lack of confidence in the project.
The phase III Neuro-TTR trial is in patients with familial amyloid polyneuropathy, where transthyretin (TTR) amyloid deposits cause nerve damage. It recruited 172 patients given 300mg Ionis-TTRRx subcutaneously once weekly for 64 weeks versus placebo, measuring change from baseline in neuropathy impairment score and quality of life questionnaire as co-primary endpoints.
Last May Ionis reported cases of severe thrombocytopenia in the trial, although the exact number was not disclosed; shares fell 39% (Ionis safety blow boosts Alnylam, May 27, 2016). The company put in place more frequent monitoring so the study could continue.
Safety data from Neuro-TTR has important consequences for Glaxosmithkline, which put a separate cardiomyopathy trial of the same project on hold until more data from the Neuro-TTR trial were available. If the latest readout is negative Ionis could be left in the lurch.
The data are also important for Alnylam, which is active in amyloidosis. The best-case scenario for Alnylam would be Neuro-TTR success but with unfavourable safety; if Neuro-TTR simply shows little benefit this could increase investor doubts over the RNAi/antisense TTR knockdown hypothesis.
Alnylam had its own setback when revusiran, a TTR RNAi project, was discontinued after deaths occurred in its phase III trial in cardiomyopathy due to hereditary ATTR amyloidosis (Alnylam failure puts RNAi under the spotlight again, October 6, 2016). Its attention now turns to patisiran, with data from the Apollo trial in polyneuropathy also expected mid-year.
Novartis gained RTH258, an anti-VEGF antibody fragment also known as brolucizumab, through its acquisition of Alcon.
Its first pivotal data are expected mid-year from the Hawk and Harrier studies, respectively in 990 and 860 patients with age-related macular degeneration. The primary endpoint for both is change in best corrected visual acuity from baseline at week 48, in both cases against 2mg Eylea.
In phase II RTH258 showed itself non-inferior to Eylea in a 173-patient study measuring change in visual acuity after 12 weeks (Novartis sees past Lucentis’s decline, March 3, 2015).
However, RTH258 is not expected to be filed until next year because, though pivotal data should be available sooner, additional CMC work is required, Novartis has said. According to its first-quarter results a filing in diabetic macular oedema will also come in 2020.
Leerink analysts believe that RTH258 will show non-inferiority in the latest trials; however they do not think it will get approval for three-month dosing. Timing for re-treatment in the trial is physician rather than protocol-driven, and it is likely that only a small population will actually be managed on the less-frequent dosing schedule.
The potentially modest commercial advantage is reflected in consensus downgrades, with 2022 sales now at $184m, according to EvaluatePharma – they once hit $573m. Lucentis sales are sinking from a peak of $4.3bn in 2014 to a forecast $2bn by 2022, with Novartis expected to book $1.2bn and Roche the rest. RTH258 looks like it will struggle to make up the shortfall.